Obesity is a well known risk factor for the initiation and perpetuation of knee osteoarthritis . This association is obvious because any overload on a weight-bearing joint would provoke tear and wear at the surface of cartilage. In recent years, this simplistic view of the pathophysiologic features of osteoarthritis has been greatly transformed, thanks to the discovery of a central role of inflammation in osteoarthritis . Inflammatory mediators such as cytokines, lipid derivatives, reactive oxygen species or advanced-glycation end products can be produced and activate cells from joint tissues (mainly synovium, cartilage and subchondral bone), thus leading to the release of matrix metalloproteinases (MMPs) into the joint cavity and eventually cartilage degradation . More recently, strong epidemiological data have shown that the risk of hand osteoarthritis is about two-fold in people with obesity as compared with normal-weight people . Thus, the role of obesity in osteoarthritis is much more complex than previously thought because overload cannot completely explain the risk [5,6]. Systemic factors must be involved, which led to the hypothesis that adipokines, cytokines mainly produced by the adipose tissue, could play a role, at least in osteoarthritis of the hand but potentially other locations . More recently, studies have demonstrated increased risk of osteoarthritis in obese patients with metabolic syndrome (MetS) compared with obese patients without MetS . The discovery of a new phenotype linking osteoarthritis and low-grade inflammation related to obesity is a great excitement in the field because it opens a new area of research in the fields of pathophysiology, diagnosis, prognosis, treatments and prevention [9▪▪]. This review summarizes original published results related to osteoarthritis, obesity and inflammation.
MEDLINE was searched via PubMed for English-language original articles published between January 2011 and July 2012 with the search terms ‘osteoarthritis and inflammation’, ‘osteoarthritis and obesity’. Relevant references from selected publications and relevant articles published before January 2011 were identified.
MECHANICS AND INFLAMMATION IN OBESITY
The increased mechanical load is an essential component in obesity-associated osteoarthritis of weight-bearing joints. Moreover, numerous studies focused on the importance of the mechanical stimulus in joint physiology. Interestingly, recent data link mechanical stress to inflammation in osteoarthritis by the presence of mechanoreceptors at the surface of chondrocytes , which may explain why in a recent study , compressive stress on cartilage explants induced the expression of IL-8/Kc. Synovial membrane and subchondral bone are also submitted to mechanical stress. Mechanical stretch enhances the expression of COX-2 and IL-1β and the amount of PGE2 synthesis in fibroblast-like synoviocytes . It further increases the production of MMP-2 induced by inflammatory stimuli in fibroblasts . Subchondral bone sclerosis is an important feature of osteoarthritis. Osteoblasts from the sclerotic areas of osteoarthritis subchondral bone show an altered phenotype with higher expression of inflammatory mediators as compared with osteoblasts from nonsclerotic areas . Interestingly, Sanchez et al. [15▪▪] recently showed that this peculiar phenotype can be mimicked by mechanical loading of osteoblasts from nonsclerotic areas of osteoarthritis subchondral bone. Compression indeed increased expression of genes coding for IL-6, cyclooxygenase 2, RANKL, FGF-2, and IL-8, as well as MMP-3, MMP-9, and MMP-13 but reduced expression of osteoprotegerin [15▪▪].
IN-VITRO AND IN-VIVO EXPERIMENTAL STUDIES
Several studies have used high-fat fed animals to investigate the aggravating role of obesity in knee osteoarthritis independently of overweight status. In vitro, knee cartilage from rabbits fed a high-fat diet showed lower glycosaminoglycan content and aggrecanase-1 expression than cartilage from rabbits fed a normal-fat diet, independently of animal weight . In a posttrauma osteoarthritis model (closed intra-articular fracture of one knee at week 16), mice fed a high-fat diet from 4 weeks of age showed higher osteoarthritis cartilage degeneration at 8 weeks postfracture than those fed a normal diet . Interestingly, in another posttrauma mouse model (destabilization of the medial meniscus with transection of the medial collateral ligament), Mooney et al.  demonstrated that the accelerated osteoarthritis progression seen in animals on high-fat diet was not correlated with weight gain. Whereas there was a significant weight gain between a short and a long-term high-fat diet, histological osteoarthritis parameters were comparably accelerated relative to those of lean controls. Such a result was strengthened by Gierman's study  showing lack of correlation between osteoarthritis severity and body weight in an original experimental model of mice transgenic for human C-reactive protein (CRP) on a high-fat diet. Use of this model revealed a positive correlation between the induction of CRP evoked by the high-fat diet on day 3 and osteoarthritis grade at endpoint. Moreover, addition of treatment with anti-inflammatory properties (Rosuvastatin and Rosiglitazone) to high-fat diet induced an inhibition of osteoarthritis histologic lesions in male mice. These data suggest that obesity-induced low-grade inflammation is critical for inducting osteoarthritis. Indeed, a very high-fat diet in mice causes, in parallel, osteoarthritis and systemic inflammation such as increased levels of leptin, adiponectin, Kc/IL-8, CXCL9 and IL-1RA [20▪▪]. Surprisingly, when animals are placed on a wheel-running exercise plan, progression of knee osteoarthritis is reduced, without reducing body fat, which suggests that increased aerobic exercise may act independently of weight loss in promoting joint health.
Adipokines are cytokines mainly produced by adipose tissue and released into the blood . One of their principal roles is to modulate the metabolism, satiety and their dysfunctions have been implicated in some forms of obesity .
The main adipokines with a demonstrated role in osteoarthritis, at least in vitro, are leptin, adiponectin, resistin, nicotinamide phosphoribosyltransferase (NAMPT)/visfatin, lipocalin-2 and SAA3 [23,24] (Fig. 1). Chemerin is a recently described chemokine but also an adipokine that regulates adipocyte development and metabolic function, as well as glucose metabolism in liver and skeletal muscle tissues [25,26]. Chemerin is detected in osteoarthritis synovial fluid with levels linked to disease severity . In joints, chemerin can be expressed by chondrocytes  and fibroblast-like synoviocytes . Moreover, chemerin significantly increases Toll-like receptor 4 mRNA and synthesis of CCL2 in osteoarthritis fibroblast-like synoviocytes , whereas it stimulates proinflammatory cytokines and matrix metalloproteinase release in chondrocytes .
The effect of adipokines on the osteoarthritis process is in general controversial. For leptin, its role is mainly catabolic although the pioneer study  showed anabolic effect. Leptin, alone or in synergy with IL-1, induced collagen release from bovine cartilage explants and upregulated MMP-1 and MMP-13 expression in bovine chondrocytes . However, NAMPT/visfatin is generally considered an inflammatory and pro-degradative adipokine [32,33]. A new study  showed that NAMPT/visfatin may inhibit matrix synthesis by articular chondrocytes and counteract IGF-1 function in chondrocytes by activating the erk/MAPK pathway independently of the IGF-1 receptor. Moreover, visfatin, but not leptin, increased MMP activity, nitric oxide (NO) production and proteoglycan release in porcine cartilage explants . Interestingly, these results were reproduced in meniscus explants.
The discrepancy in the literature as to the effect of adipokines may be explained by differential expression of adipokines and their receptors depending on the differentiation state of chondrocytes. Monolayer culture downregulated adiponectin and leptin but upregulated their receptors [36▪]. Interestingly, neutralization of leptin induced a loss of chondrocyte phenotype, which suggests that adipokines themselves can modulate chondrocyte differentiation [36▪].
ADIPOKINES AS BIOMARKERS FOR OSTEOARTHRITIS
Being able to provide diagnostis or prognosis of osteoarthritis at an early stage is a great challenge for the future of therapy and prevention . Adipokine concentration testing has been recently assessed for this aim in hand and knee osteoarthritis. In hand osteoarthritis, serum levels of adiponectin, but not leptin or resistin, were associated with disease progression in assessing baseline and 6-year radiographs of joint space narrowing in 164 patients . However, Choe et al.  showed higher serum levels of resistin, but not adiponectin, in radiographic subchondral erosion than in non-radiographic hand osteoarthritis with no difference in joint space narrowing. An absence of a relationship between leptin concentration and hand osteoarthritis has been confirmed in a cross-sectional study  from a NHANES III sample.
In knee osteoarthritis, baseline serum level of leptin receptor but not leptin was associated with reduced levels of the cartilage formation biomarker PIIANP, increased cartilage defect score and increased cartilage volume loss assessed by MRI in 117 patients over 2 years . In contrast, a baseline serum level of leptin was associated with bone formation biomarkers (osteocalcine and N-terminal propeptide of human procollagen type I) . Plasma adiponectin levels were higher in patients undergoing total knee replacement surgery, when preoperative radiographs showed the most severe lesions, than in patients with less severe disease . However, the literature is somewhat confusing in such a population: de Boer et al.  assessed adipokine concentration in a similargroup of 172 patients and did not find any association of adiponectin and resistin serum level with cartilage damage, only with synovial inflammation.
A NEW SOURCE OF ADIPOKINES: THE INFRAPATELLAR FAT PAD
White adipose tissue is the most common, known source of adipokines, but joint tissues are also a source. For example, osteoarthritis cartilage can release adiponectin  and, as described above, chemerin can be produced by chondrocytes and fibroblast-like synoviocytes [28,29]. Another recent source of adipokines has been recently described as the infrapatellar fat pad (IFP). IFP, also known as Hoffa's fat pad, is a piece of fat situated within the knee, under the patella, behind patellar tendon and joint capsule and in front of femoral condyles and tibial plateau. It is described as intracapsular but extra synovial, the synovial membrane lining its posterior surface.
Because of its close relationship with joint tissues, this adipose tissue may play a role by releasing inflammatory mediators reaching the synovium and cartilage . Indeed, as compared with subcutaneous adipose tissue (ScAT) from the same osteoarthritis patients, IFP secretes high amounts of IL-6, TNF-α, adipsin, adiponectin and visfatin [44▪]. This may result primarily from the increased stromal vascular fraction (SVF) found in IFP. Cell composition of SVF only shows an increased proportion of mast cells in IFP as compared with ScAT, whereas the proportion of T-cells decreases without any difference in their phenotype [44▪]. A microarray analysis comparing the expression of multiple genes in IFP from end-stage and early-stage osteoarthritis tissue showed increased expression of genes of adipogenesis in end-stage tissue, but results for inflammatory cytokines were too heterogeneous for definitive conclusions . Interestingly, IFP cytokine production was increased by IL-1β and decreased by a PPARα agonist . Conditioned media from cultured IFP from osteoarthritis patients modulated matrix component release and MMP expression in chondrocytes but controversial results were reported. Indeed, Hui et al.  showed that conditioned media from osteoarthritis IFP induced the production of collagenase (MMP-1, MMP-13) by human chondrocytes in culture, whereas Bastiaansen-Jenniskens et al.  showed a decrease in the catabolic profile of bovine cartilage after stimulation by osteoarthritis IFP conditioned media (decreased release of NO and glycosaminoglycans and decreased expression of MMP-1).
The link between osteoarthritis, inflammation and obesity is now well established. However, whether targeting inflammation-induced obesity in humans is an appropriate treatment remains unknown. Patients who lose a lot of weight show an association of pain and function improvements, with decreased low-grade inflammation [48▪]. However, the association does not imply causality. Preclinical studies targeting adipokines are expected to bring new hope for patients, especially those with MetS.
Conflicts of interest
The authors declare no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (p. 154).
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